Voltage-gated calcium channels.

Abstract

Voltage-gated calcium (Ca(2+)) channels are key transducers of membrane potential changes into intracellular Ca(2+) transients that initiate many physiological events. There are ten members of the voltage-gated Ca(2+) channel family in mammals, and they serve distinct roles in cellular signal transduction. The Ca(V)1 subfamily initiates contraction, secretion, regulation of gene expression, integration of synaptic input in neurons, and synaptic transmission at ribbon synapses in specialized sensory cells. The Ca(V)2 subfamily is primarily responsible for initiation of synaptic transmission at fast synapses. The Ca(V)3 subfamily is important for repetitive firing of action potentials in rhythmically firing cells such as cardiac myocytes and thalamic neurons. This article presents the molecular relationships and physiological functions of these Ca(2+) channel proteins and provides information on their molecular, genetic, physiological, and pharmacological properties.

Subunit structure of Ca2+ channels. The structures of Ca2+ channel subunits are illustrated as transmembrane folding models; predicted α helices are depicted as cylinders; the lengths of lines correlate approximately to the lengths of the polypeptide segments represented; and the zigzag line on the δ subunit illustrates its glycophosphatidylinositol anchor.

Three-dimensional architecture of Ca2+ channels. (A) Illustration of the skeletal muscle CaV1.1 channel based on cryo-electronmicroscopy. This drawing assumes pseudo-fourfold symmetry of the α1 subunit. The view shows the extracellular side with the α2 subunit. The α1, γ, and δ subunits are embedded into the lipid membrane (not shown), which separates the extracellular α2 subunit from the cytosol. α2 is anchored via the disulfide-linked δ subunit within the α1 subunit. The proposed model allows for a tight interaction between α1 and δ as well as α1 and γ. (B) Structure of the CaVβ subunit with the α interaction domain (AID). Coordinates are for the CaVβ2a–CaV1.2 AID complex with SH3 (green) and NK (blue) domains are indicated. V1, V2, and V3 show the locations of the three variable domains that are absent from the structure. The AID (red) binds to a deep groove in the NK domain. AID residues tyrosine, tryptophan, and isoleucine are shown as CPK. The remaining residues are shown as lines.